CCK antagonists

ABSTRACT

In general, the invention features compounds having the formula ##STR1## or a pharmaceutically acceptable salt thereof, wherein each R 1  is, independently, an alkyl group having 1-5, inclusive, carbon atoms, an alkoxy group having 1-5, inclusive, carbon atoms, a halogen, amino, hydroxy, nitro, cyano, carboxyl, trifluoreomethyl, ethyl carboxylate, or a hydrogen; m is an integer between 0 and 2, inclusive; and A is either ##STR2## where n is an integer between 1 and 5, inclusive, and R 2  is hydroxy, an alkoxy group having 1-5, inclusive, carbon atoms, aralkoxy, aralkyl, amino, and alkyl group having 1-5, inclusive, carbon atoms, an alkylamino group having 1-5, inclusive, carbon atoms, a dialkylamino group with each alkyl group, independently having 1-5, inclusive, carbon atoms, a cycloalkylamino group wherein the ring has 4-6, inclusive, carbon atoms, or morpholino; or A is an alkyl group having 1-5, inclusive, carbon atoms, a hydroxyalkyl group having 1-5, inclusive, carbon atoms, an alkoxyalkyl group having 2-8, inclusive, carbon atoms, an aralkoxyalkyl having 8-14, inclusive, carbon atoms, an aryl group having 6-14, inclusive, carbon atoms, an aralkyl group having 6-14, inclusive, carbon atoms, and a cycloalkyl group having 3-12, inclusive, carbon atoms.

This application is a continuation-in-part of Kim U.S. patent application Ser. No. 815,217, filed Dec. 31, 1985, now U.S. Pat. No. 4,814,463.

BACKGROUND OF THE INVENTION

This invention relates to cholecystokinin (CCK) antagonists.

Chang et al., 230 Science 177 (1985), describes CCK as "a hormonal regulator of pancreatic and gastric secretion, contraction of the gallbladder, and gut motility", and states that "CCK also exists in the brain and may have an equally important role as a central nervous system transmitter". Chang et al. further mentions that CCK antagonists have "potential therapeutic utilities" and describes the compound asperlicin, which has the structure ##STR3## as a CCK antagonist.

Rovati et al., U.S. Pat. No. 4,000,297, discloses compounds of the structure ##STR4## in which R includes mono and poly substituted phenyl groups, and R¹ includes hydroxyl, an aniline group substituted at the para position with a carboxylic acid or ester thereof, an amino group substituted with phenylacetic acid or ester derivative thereof, or an alkoxy group terminating with an amino group. The compounds are described as having an antispastic effect on the smoother muscle of the gastroenteric tract, as regulating gastric secretion, and as being protective of gastroenteric mucosa.

SUMMARY OF THE INVENTION

In general, the invention features compounds having the formula: ##STR5## or a pharmaceutically acceptable salt thereof, wherein each R¹ is, independently, an alkyl group having 1 to 5, inclusive, carbon atoms, an alkoxy group having 1 to 5, inclusive, carbon atoms, a halogen, amino, hydroxy, nitro, cyano, carboxyl, trifluoromethyl, ethyl carboxylate, or a hydrogen; m is an integer between 0 and 2, inclusive; and A is either ##STR6## where n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1 to 5, inclusive, carbon atoms, aralkoxy (e.g., benzyloxy), aralkyl (e.g., benzyl), amino, an alkyl group having 1 to 5, inclusive, carbon atoms, an alkylamino group having 1 to 5, inclusive, carbon atoms, a dialkylamino group with each alkyl group, independently having 1 to 5, inclusive, carbon atoms, a cycloalkylamino group wherein the ring has 4 to 6, inclusive, carbon atoms (e.g., pyrrolidino, piperidino, N-methylpiperazino), or morpholino; or A is an alkyl group having 1 to 5, inclusive, carbon atoms, a hydroxyalkyl group having 1 to 5, inclusive, carbon atoms, an alkoxyalkyl group having 2 to 8, inclusive, carbon atoms, an aralkoxyalkyl group having 8 to 14, inclusive, carbon atoms, an aryl group (e.g., phenyl, toluyl) having 6 to 14, inclusive, carbon atoms, an aralkyl group (e.g., benzyl, phenylethyl) having 6 to 14, inclusive, carbon atoms, and a cycloalkyl group having 3 to 12, inclusive, carbon atoms.

In preferred embodiments of the invention, the tryptophan residue is of the L-configuration, the R¹ 's are either both hydrogen, both chloro (at the 3 and 4 position of the ring), or one hydrogen and one chloro or one fluoro (at the 4 position). Preferred compounds of the invention include N-benzoyl-L-tryptyl-N'-benzylglycine, N-benzoyl-L-tryptyl-N'-benzylglycine ethylester, N-benzoyl-L-tryptyl-N'-benzylqlycineamide, N-(4-chlorobenzoyl)-L-tryptyl-N'-benzylglycine, N-(4-chlorobenzoyl)-L-tryptyl-N'-benzylglycine ethylester, N-(4-chlorobenzoyl)-L-tryptyl-N'-benzylglycineamide, N-(3, 4-dichlorobenzoyl)-L-tryptyl-N'benzylglycineamide, N-(3, 4-dichloro-benzoyl)-L-tryptyl-N'-benzylglycine ethylester, N-(3, 4-dichlorobenzoyl)-L-tryptyl-N'-benzylglycineamide, N-benzoyl-L-tryptyl-N'-benzyl-N'-methylamide, N-(4-chlorobenzoyl)-L-tryptyl-N'-benzyl-N'-methylamide, N-(3, 4-dichlorobenzoyl)-N'-benzyl-N'-methylamide; N-(4-fluorobenzoyl)-L-tryptyl-N'-benzylglycine ethyl ester; N-(4-fluorobenzoyl)-L-tryptyl-N'-benzylglycine; N-(3,4-dichlorobenzoyl)-L-tryptyl-N'-phenylethylqlycine ethylester; N-(3,4-dichlorobenzoyl)-L-tryptyl-N'-phenylethylglycine; N-(4-fluorobenzoyl)-L-tryptyl-N'-phenylethylglycine ethylester; N-(4-fluorobenzoyl)-L-tryptyl-N'-phenylethylglycine; or pharmaceutically acceptable salts thereof.

In other preferred embodiments, a therapeutically effective amount of the therapeutic compound and a pharmaceutically acceptable carrier substance, e.g., magnesium carbonate or lactose, form a therapeutic composition, e.g., a pill, tablet, capsule, or liquid, for oral administration to a patient; a liquid or an ointment capable of being administered transdermally, nasally, rectally, or sublingualy; a liquid capable of being adminstered intravenously, parenterally, subcutaneously, or intraperitonally; or an oral or a parenteral sustained release formulation.

The compounds of the invention are effective cholecystokinin antagonists and as such are effective in treating acute pancreatitis; in treating gastric, peptic, and duodenal ulcers; and in suppressinq appetite. They are also effective, alone or in combination with other chemotherapeutic agents, in the treatment of pancreatic cancers; this activity is believed to occur because of antagonism to the action of cholecystokinin in inducing pancreatic hyperplasia in the presence of known carcinogens, e.g., nitrosamine. The compounds are stable, inexpensive to make, and non-toxic.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

We now describe the structure, synthesis, and use of preferred embodiments of the invention.

Structure

The compounds of the invention have the general formula recited in the summary of the invention above. Examples of preferred compounds within this formula are those referred to as preferred embodiments above.

The compounds of the invention are N-substituted (D- or L-) tryptyl N'-disubstituted glycine or N-substituted (D- or L-) tryptyl N'-disubstituted amide derivatives.

The compounds can also be provided in the form of pharmaceutically acceptable salts. Examples of suitable salts include those formed with hydrochloric, hydrobromic, sulfuric, maleic, acetic, or fumaric acid; potassium, sodium, or aluminum hydroxide; or dicyclohexylamine.

Synthesis

The above compounds can be synthesized as follows. First, a compound of formula (2) ##STR7## where X represents a hydroxyl or carboxylic acid activating group, e.g., a halogen such as chlorine, and R¹ is defined as above, is condensed with a secondary amino compound of formula (3) ##STR8## where m and A are defined as before.

The corresponding acids are then prepared from these esters by hydrolyzing the esters with aqueous base. Amides can be prepared by treating the corresponding esters with ammonia or an amine.

Compounds within formulae (2) and (3) are commercially available; alternatively they can be synthesized according to standard methods, e.g., as described in Greenstein, et al., Chemistry of the Amino Acids, Vols. 1-3, J. Wiley, New York (1961); J. Pharm. Sci., 51, 1058 (1962); Org. Reaction 5, 301 (1949); J. Chem. Soc. (c), 2223 (1969); and J. Org. Chem., 37, 1673 (1972).

The condensation reactions are preferably carried out in an inert organic solvent, e.g., dimethylformamide, dichloromethane, tetrahydrofuran, benzene, or acetonitrile, using a suitable mild condensing agent, e.g., thionylchloride, oxalylchloride, or dicyclohexylcarbodiimide (DDC), and optionally a catalyst, e.g., 1-hydroxybenzotriazole (HOBT). The reaction temperature is maintained below room temperature (-15° C. to room temperature) in order to minimize side reactions. Typical condensation procedures are described in Schroeder et al., The Peptides, Vols. 1-2 (1965, 1966) and Gross et al., The Peptides, Vols. 1-3 (1979, 1980, 1981).

The intermediate and final products are isolated and purified by standard methods e.g., column chromatography or crystallization. Purity is determined using chromatographic, spectroscopic, and chemical analysis.

Specific compounds are made as follows.

N-Benzoyl-L-tryptyl-N'-benzylqlycine ethylester

The first step is the preparation of N-benzoyl-L-tryptophan, as follows. 10 ml benzoyl chloride and 45 ml 2N NaOH are added, in several and alternate portions, to a vigorously stirred and ice-cooled solution of 17 g L-tryptophan in 41 ml 2N NaOH. The solution is maintained at an alkaline pH by the addition of extra base when necessary. Upon completion of the addition of reagents, the mixture is stirred at room temperature for 1 hour, after which it is acidified to pH 1-2 with HCl. The crude product is dried and then triturated with cold ether to give 20 g of the product as a colorless solid. TLC: (silica gel; CHCl₃ /MeOH/HOAc=6:1:0.25) Rf=0.53.

A cold solution of 1.44 g dicyclohexylcarbodiimide in 4 ml dimethylformamide is added to a stirred ice-cooled solution of 2.0 g N-benzoyl-L-tryptophan and 1.26 g N-benzylglycine ethylester in 8 ml dry dimethlformamide. The resulting mixture is stirred at 0° for 1 hour and then at room temperature overnight. It is then filtered and the solvent is evaporated to dryness in vacuo. The residue is partitioned between chloroform and water. The chloroform layer is washed with 5% aqueous NaHCO₃ and water, and then dried over anhydrous MgSO₄. After evaporation of solvent, the residue is chromatoqraphed on silica gel (250 g) using chloroform/acetone (19:1). Appropriate fractions are pooled and the solvent removed in vacuo to yield 1.55 g of the product as a foam. TLC: (silica gel; CHCl₃ /acetone=9:1) Rf=0.35.

N-Benzoyl-L-tryptyl-N'-benzylqlycineamide

490 mg N-benzoyl-L-tryptyl-N'-benzylglycine ethylester is dissolved in 10 ml saturated methanolic ammonia, and the solution is kept at room temperature in a pressure bottle overnight. Excess ammonia and solvent are then removed in vacuo, and the residue is recrystallized from ethanol to yield 286 mg of the crystaline product. m.p. 203°-204° ; TLC: (silica gel; CHCl₃ /MeOH=9:1) Rf=0.47.

N-Benzoyl-L-tryptyl-N'-benzylqlycine

500 mg N-benzoyl-L-tryptyl-N'-benzylglycine ethylester is dissolved in 5 ml ethanol and treated with 1 ml 2N NaOH. After stirring at room temperature for 1 hour, the solution is diluted with water, acidified to pH 1-2 with 2N HCl, and extracted with ethylacetate (3×50 ml). The combined extracts are dried over anhydrous MgSO₄, and solvent is removed in vacuo to yield 440 mg of the product as a foam. TLC: (silica gel; CHCl₃ /MeOH/HOAc=6:1:0.25) Rf=0.6.

N-(3,4-Dichlorobenzoyl)-L-tryptyl-N'-benzylqlycine ethylester

The first step is the preparation of N-(3,4-dichlorobenzoyl)-L-tryptophan in an analogous manner to the preparation of N-benzoyl-L-tryptophan except substituting 3, 4-dichlorobenzoyl chloride (dissolved in either dioxane, tetrahydrofuran, or acetone) for benzoyl chloride.

A cold solution of 1.74 g dicyclohexylcarbodiimide in 2 ml dimethylformamide is added to a stirred ice-cooled solution of 3.0 g N (3,4-dichlorobenzoyl)-L-tryptophan, 1.55 g N-benzylqlycine ethylester, and 2.16 g 1-hydroxybenzotriazole in 10 ml dimethylformamide. The mixture is stirred at 0° C. for 1 hour and then at room temperature for 2 hours. It is then filtered, and the solvent is evaporated in vacuo to dryness. The residue is dissolved in chloroform, washed with 5% aqueous NaHCO₃ and water, and dried over anhydrous MgSO₄. Solvent is evaporated in vacuo to dryness, and the residue is dissolved in chloroform, washed with 5% aqueous NaHCO₃ and water, and dried over anhydrous MqSO₄. After evaporation of solvent, the residue is chromatographed on silica gel (260 g) usinq CHCl₃ /acetone (40:1) as the eluent. Appropriate fractions are pooled and the solvent removed in vacuo to yield 2.4 g of the product as a colorless solid. m.p. 190°-192°; TLC: (silica gel: CHCl₃ /acetone=9:1) Rf=0.42.

N-Benzoyl-L-tryptyl-N'-benzyl-N'-methylamide

A cold solution of 0.5 g dicyclohexylcarbodiimide in 2 ml dichloromethane is added to a stirred ice-cooled solution of 0.6 g N-benzoyl-L-tryptophan and 0.3 g N-benzylmethylamine in dichloromethane dimethylformide (2:1, 20 ml.). The mixture is stirred at 0° C. for 1 hour and then at room temperature overnight. It is then filtered and the solvent evaporated in vacuo to dryness. The residue is partitioned between chloroform and water. The chloroform layer is washed with 5% NaHCO₃ and water, and then dried over anhydrous MgSO₄. After evaporation of solvent, the residue is chromatographed on silica gel (35 g) using chloroform/acetone (19:1). Appropriate fractions are pooled and the solvent removed in vacuo to yield 0.57 g of the product as colorless solid. m.p. 65°-68°; TLC: (silica qel; CHCl₃ /acetone =4:0) Rf=0.45.

N-(3,4-Dichlorobenzoyl)-L-tryptyl-N'-phenylethyl-glycine ethylester

The first step is the preparation of N-phenyl-ethylqlycine ethylester, as follows. To a solution of 1.25 ml phenylethylamine in 10 ml chloroform is added with stirring 0.56 ml ethylbromoacetate. After two hours, the precipitate is filtered off and the solvent is removed in vacuo to dryness. The residue is further triturated with ether, the precipitate is filtered off and the filtrate is concentrated in vacuo to give 1.0 g product as an oil. TLC: (Silica qel; CHCl₃ /acetone=9:1) Rf=0.29.

A cold solution of 0.29 g dicyclohexylcarbodiimide in 4 ml dimethylformide is added to a stirred ice-cold solution of 0.51 g N-(3,4-dichlorobenzoyl)-L-tryptophan, 0.31 g N-phenylethylglycine ethylester, and 0.36 g 1-hydroxybenzotriazole in 11 ml dimethylformide. The mixture is stirred at 0° C. for one hour and then at room temperature overnight. It is then filtered, and the solvent is evaporated in vacuo to dryness. The residue is dissolved in chloroform, washed with 5% aqueous NaHCO₃ and water, and dried over anhydrous MgSO₄. After evaporation of solvent, the residue is chromatographed on silica gel (55 g) using chloroform as the eluent. Appropriate fractions are pooled and the solvent removed in vacuo to yield 0.58 g of the product as a pale yellow solid. TLC: (silica gel: CHCl₃ /acetone=9:1) RF=0.43.

N-(3,4-Dichlorobenzoyl)-L-tryptyl-N -phenylethylqlycine

350 mg N-(3,4-dichlorobenzoyl)-L-tryptyl-N'-phenylethylqlycine ethylester is dissolved in 8 ml ethanol and treated with 1 ml 2N NaOH. After stirring at room temperature for one hour, the solution is diluted with water, acidified to pH 1-2 with 2N HCl, and the resulting precipitate is collected by filtration. TLC: (silica qel; CHCl₃ /MeOH/HOAc=15:1:0.28) Rf=0.38.

Use

When administered to a patient (e.g., orally, intravenously, parenterally, nasally, or by suppository), the compounds are effective in the treatment of gastric, peptic, and duodenal ulcers; in the treatment of acute pancreatitis; and in suppressinq appetite.

The compounds can be administered to a human patient in a dosage of 0.1-50 mg/kg/day, preferably about 0.1 mg/kg/day when administered parenterally and about 50 mg/kg/day when administered orally.

Other embodiments are within the following claims. 

I claim:
 1. A compound having the formula ##STR9## or pharmaceutically acceptable salt thereof, wherein each R¹ is, independently, an alkyl group having 1-5, inclusive, carbon atoms, an alkoxy group having 1-5, inclusive, carbon atoms, a halogen, amino, hydroxy, nitro, cyano, carboxyl, trifluoromethyl, ethyl carboxylate, or a hydrogen;m is an integer between 0 and 2, inclusive; A is either ##STR10## p10 wherein n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1-5, inclusive, carbon atoms, aralkoxy, aralkyl, amino, an alkyl group having 1-5, inclusive, carbon atoms, an alkylamino group having 1-5, inclusive, carbon atoms, a dialkylamino group with each alkyl group having 1-5, inclusive, carbon atoms, or A is an alkyl group having 1-5, inclusive, carbon atoms, a hydroxalkyl group having 1-5, inclusive, carbon atoms, an alkoxyalkyl group having 2-8, inclusive, carbon atoms, an aralkoxyalkyl having 8-14, inclusive, carbon atoms, an aryl group having 6-14, inclusive, carbon atoms, an aralkyl group having 6-14, inclusive, carbon atoms, and a cycloalkyl group having 3-12, inclusive, carbon atoms.
 2. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, both R¹ 's are H, m is 1, and A is ##STR11## said compounds having the name N-benzoyl-L-tryptyl-N'-benzylglycine; or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, both R¹ 's are H, m is 1, and A is ##STR12## said compound having the name N-benzoyl-L-tryptyl-N'-benzyqlycine ethylester; or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, both R¹ 's are H, m is 1, and A is ##STR13## said compound having the name N-benzoyl-L-tryptyl-N'-benzylglycineamide; or a pharmaceutically acceptable salt thereof.
 5. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, one R¹ is H, the other R^(`) is 4-chloro, m is 1, and A is ##STR14## said compound having the name N-(4-chlorobenzoyl)-L-tryptyl-N'-benzylglycine; or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 1, wherein the tryptophan residue is of the L-configuration, one R¹ is H, the other R¹ is 4-chloro, m is 1, and A is ##STR15## said compound having the name N-(4-chlorobenzoyl)-L-tryptyl-N'-benzylglycine ethylester; or a pharmaceutically acceptable salt thereof.
 7. The compound of claim 1, wherein the tryptophan residue is of the L-configuration, one R¹ is H, the other R¹ is 4-chloro, m is 1, and A is ##STR16## said compound having the name N-(4-chlorobenzoyl)-L-tryptyl-N'-benzylglycineamide; or a pharmaceutically acceptable salt thereof.
 8. The compound of claim 1, wherein the tryptophan residue is of the L-configuration, one R¹ is 3-chloro, the other R₁ is 4-chloro, m is 1, and A is ##STR17## said compound having the name N-(3,4-dichlorobenzoyl)-L-tryptyl-N'-benzylglycine; or a pharmaceutically acceptable salt thereof.
 9. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, one R¹ is 3-chloro, the other R¹ is 4-chloro, m is 1, and A is ##STR18## said compound having the name N-(3, 4-dichlorobenzoyl)-L-tryptyl-N'-benzylglycine ethylester; or a pharmaceutically acceptable salt thereof.
 10. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, one R¹ is 3-chloro, the other R¹ is 4-chloro, is 1, and A is ##STR19## said compound having the name N-(3, 4-dichlorobenzoyl)-L-tryptyl-N'-benzylglycineamide; or a pharmaceutically acceptable salt thereof.
 11. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, both R¹ 's are H, m is 1, and A is --CH₃, said compound having the name N-benzoyl-L-tryptyl-N'-benzyl-N'-methylamide; or a pharmaceutically acceptable salt thereof.
 12. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, one R¹ is H, the other R₁ is 4-chloro, m is 1, and A is --CH₃ said compound having the name N-(4-chlorobenzoyl)-L-tryptyl-N'-benzyl-N'-methylamide; or a pharmaceutially acceptable salt thereof.
 13. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, one R₁ is 3-chloro, the other R₁ is 4-chloro, m is 1, and A is --CH₃, said compound having the name N-(3,4-dichlorobenzoyl)-L-tryptyl-N'-benzyl-N'-methylamide; or a pharmaceutically acceptable salt thereof.
 14. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, one R' is 3-chloro, the other R' is 4-chloro, m is 2 and A is ##STR20## said compound having the name N-(3,4-dichlorobenzoyl)-L-tryptyl-N'-phenylethyl qlycine ethylester; or a pharmaceutically acceptable salt thereof.
 15. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, one R' is 3-chloro, the other R' is 4-chloro, m is 2 and A is ##STR21## said compound having the name N-(3,4-dichlorobenzoyl)-L-tryptyl-N'-phenylethylglycine; or a pharmaceutically acceptable salt thereof.
 16. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, one R' is H, the other R' is 4-fluoro, m is z, and A is ##STR22## said compound having the name N-(4-fluorobenzoyl)-L-tryptyl-N'-phenylethylglycine ethylester; or a pharmaceutically acceptable salt therof.
 17. The compound of claim 1 wherein the tryptophan residue is of the L-configuration, one R' is H, the other R' is 4-fluoro, m is z, and A is ##STR23## said compound having the name N-(4-fluorobenzoyl)-L-tryptyl-N'-phenylethylglycine; or a pharmaceutically acceptable salt thereof.
 18. The compound of claim 1, wherein said aralkoxy is benzyloxy.
 19. The compound of claim 1, wherein said R² is benzyl.
 20. The compound of claim 1 wherein said aryl group is phenyl or toluyl.
 21. The compound of claim 1 wherein said A is benzyl or phenylethyl.
 22. A method for treating a patient having a disorder associated with excessive cholecystokinin comprising administering to said patient an effective amount of the compound of any of claims 1-21.
 23. The method of claim 22 wherein said disorder is a gastric, peptic, or duodenal ulcer, or acute pancreatitis.
 24. A method for suppressinq a human patient's appetite comprising administering to said patient an effective amount of the compound of any of claims 1-21. 